Biosynthesis of the tetrapyrrole (porphyrin) ring of heme (protoporphyrin IX) starts in the mitochondrial matrix. Succinyl-CoA donated from the Krebs cycle in the mitochondria condenses with glycine from the mitochondrial pool of this amino acid to form δ-aminolevulinic acid (ALA). ALA is then exported to the cytoplasm where the enzyme δ-aminolevulinic acid dehydratase (ALAD), also called porphobilinogen (PBG) synthase, condenses two molecules of ALA to form porphobilinogen. Next, a tetrapyrrole is formed through the enzymatic action of porphobilinogen deaminase and the condensation of four molecules of PBG. Uroporphyrinogen III synthase catalyzes ring closure, converting the linear tetrapyrrole, hydroxymethylbilane, to uroporphyrinogen III, the first in a series of porphyrin intermediates that are produced by decarboxylation and oxidation reactions. Only a small fraction of the porphyrin intermediates return to the mitochondria and provide protoporphyrin IX, the precursor for heme. The rest of the porphyrins are excreted, without any apparent function.
All tissue types synthesize porphyrins and heme, although their capacities for regulation and such biosynthesis vary. The micronutrient requirements, however, of all tissues for the production of heme and porphyrins as well as the known inhibitors and inducers are identical. Heme biosynthesis in the brain, for example, varies according to the type of brain cell. Heme biosynthesis appears to be higher in non-neuronal cells and lower in neuronal cells (Whetsell, 1978). Heme and porphyrin metabolism are disturbed in Alzheimer disease (Atamna, 2004) or after exposure to environmental toxins including metals (Daniell, 1997). The mechanisms underlying these disturbances are not known, but porphyrin intermediates are excessively produced. We have previously observed that heme and heme-α deficiencies, which were induced in human cells in vitro, and in primary hippocampal neurons from rats, induced cytological changes that mimicked the cytopathology of the brain during AD (Atamna, 2002).
The Krebs cycle is an amphibolic pathway; the intermediates of the Krebs cycle supply or receive the carbon skeleton of several metabolites in anabolic and catabolic processes. The intermediates of the Krebs cycle are the precursors for several anabolic processes, including the biosynthesis of porphyrins, amino acids, purines, pyrimidines, fatty acids, sterols, and some neurotransmitters. These metabolites, except for the porphyrins, provide the Krebs cycle with the intermediates when they are turned over by the metabolic activity of the cell. Some of these metabolites such as the amino acids and fatty acids are consumed in the diet; porphyrins and heme are not bio-available from the diet and must be synthesized in situ. Therefore, in most of these metabolic activities, the Krebs cycle reclaims the complete or partial intermediates by salvage or through a recycling mechanism.
No biological function has been ascribed for the porphyrins, other than as a precursor for heme. Unlike the recycled Krebs intermediates, porphyrins are continuously excreted from the body. Porphyrins usually leave the body in two ways: 1) continuously excreted directly in the urine and 2) excreted as bile pigment when heme is turned over to bilirubin. Therefore a net efflux of succinyl-CoA from Krebs cycle occurs as porphyrins are synthesized.
The biosynthesis of one mole of heme requires 8 moles of succinyl-CoA (Ponka, 1999; Woods, 1976) from the Krebs cycle and 8 moles of glycine from the mitochondrial pool of amino acids. Because not all the porphyrin produced by the heme biosynthetic pathway becomes heme (some porphyrin side products are excreted), the quantity of succinyl-CoA that consumed from the TCA cycle for porphyrin biosynthesis exceeds 8 moles/1 mol heme. It is well known that the porphyrin synthetic pathway produces a mixture of porphyrin side products (e.g. uroporphyrin I & III, coproporphyrin I & III) (Ponka, 1999). In rodents (F-344), about 2 nmols/day (Bowers, 1992) of total porphyrins are excreted in urine; this figure increases 100-1000 fold in humans (Daniell, 1997). Only 5% of these porphyrins are converted to heme, as demonstrated in rat primary olfactory receptor neurons (Ingi, 1996). In addition, it is estimated that between 20 and 35% of newly formed heme is directly converted to bile pigments (Grandchamp, 1981), suggesting a continuous demand for heme biosynthesis. Therefore, it appears that the synthetic pathway of porphyrins is energy consuming and drains much succinyl-CoA from the Krebs cycle.
We now show that the changes in the biosynthesis of porphyrin and heme in Alzheimer's disease are a response to the pathological conditions of the brain and that porphyrins can be used in prevention and treatment of AD and other metal-related disorders.